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FLASH GENE

Symbol

NPC1L1

contributors: mct - updated : 25-10-2012

HGNC name	NPC1 (Niemann-Pick disease, type C1, gene)-like 1
HGNC id	7898

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	28.79 kb     20 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Binding site
text structure	a sterol regulatory element,transcription factor binsding sites
	important HNF1 binding site was identified within the NPC1L1 promoter and HNF1A can bind to the NPC1L1 promoter

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_013389 20 - 5066 NP_037521 148.7 1359 - 2010 20307540 delta exon 5 - - 2840 isoform 3 - - - 2004 15173162 also called delta exon 5 variant 4 - - 2570 isoform 4 80 724 - 2004 15173162 also called NPC1L1T skipping exon 7 terminating in exon 8 NM_001101648 19 - 4985 NP_001095118 - 1332 - 2010 20307540

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive gallbladder           intestine small intestine     highly Homo sapiens   liver       highly Homo sapiens   stomach         Endocrine pancreas

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular endocrine

cells

System Cell Pubmed Species Stage Rna symbol Digestive enterocyte Lymphoid/Immune histiocyte

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal domain (NTD) of NPC1L1 binds cholesterol
	conserved N-terminal “NPC1” domain, encompassing a similar cysteine-rich globular domain
	sterol sensing domain (SSD)
	YQRL motif, but lacking the dileucine targeting motif of NPC1
	a typical signal peptide and 13 membrane-spanning domains, 5 of the 13 membrane-spanning helices constitute a predicted sterol sensing domain (SSD) encompassing 180 AAs, that may be involved in sterol binding
	extensive N-linked glycosylation sites
	C-terminus projects to the cytosol

HOMOLOGY

interspecies	homolog to NPC1
	homolog to SCAP
	ortholog to HMGCR

Homologene

FAMILY

lipid transport facilitators family

CATEGORY

transport carrier

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
text	enriched in the apical membrane of small intestine absorptive enterocytes where it mediates extracellular sterol transport across the brush border membrane
	dynamic trafficking of NPC1L1 between the cell surface and intracellular compartments and suggests that this transport is involved in NPC1L1-mediated cellular sterol uptake
	can move between the endocytic recycling compartment (ERC)4 and plasma membrane (PM)
	localizes on the brush border membrane of small intestine and canalicular membrane of liver

basic FUNCTION	involved in intestinal absorption and intracellular cholesterol transport
	required for intestinal uptake of both cholesterol and phytosterols and playing a major role in cholesterol
	involved in an ezetimibe-sensitive pathway for cholesterol uptake
	has the ability to transport alpha-tocopherol
	play an essential role in intestinal cholesterol absorption
	mediates cholesterol uptake through vesicular endocytosis, and NPC1L1 recycles between endocytic recycling compartment (ERC) and plasma membrane (PM) in responding to cellular cholesterol alterations
	mediates intestinal cholesterol absorption and it may also limit hepatobiliary cholesterol excretion
	essential protein for dietary cholesterol absorption
	mediates cholesterol uptake via vesicular endocytosis
	playing a crucial role in dietary and biliary cholesterol absorption
	senses cholesterol through direct binding by its NTD, then cholesterol may be transferred to local membrane to form the NPC1L1-flotillin-cholesterol membrane microdomain, which is internalized via the clathrin-AP2 pathway
	function of NPC1L1 in reabsorbing biliary cholesterol was impaired when hepatic CDC42 was deleted

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

cellular trafficking transport

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule

protein	NR1H3 target gene further supporting a crucial role of NR1H3 in intestinal cholesterol homeostasis
	functional role of FLOT1, FLOT2 in NPC1L1-mediated cholesterol uptake, elucidating the formation of NPC1L1-FLOT1, FLOT2-positive cholesterol-enriched membrane microdomains as a mechanism for efficient cholesterol absorption
	CDC42 controls the cholesterol-regulated transport and localization of NPC1L1, and plays a role in cholesterol absorption
	apical PYY was able to decrease cholesterol uptake via NPC1L1 downregulation

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

Susceptibility

to poor LDL-C response to treatment with ezetimibe co-administrated with statin to low absorption of cholesterol to hypercholesterolemia

Variant & Polymorphism SNP , other	associated to poor LDL-C response to treatment with ezetimibe co-administrated with statin
	variants associated with reduced sterol absorption and plasma low-density lipoprotein levels
	NPC1L1 gene promoter variant is associated with autosomal dominant hypercholesterolemia

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed metabolism lipid cholesterol useful drug target for the treatment of hypercholesterolemia and sitosterolemia diabete metabolic syndrom   NPC1L1 inhibition has been shown to have beneficial effects on components of the metabolic syndrome, such as obesity, insulin resistance, and fatty liver, in addition to atherosclerosis

ANIMAL & CELL MODELS

NPC1L1-deficient mice show dramatic reductions in dietary cholesterol absorption